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Publication Abstract from PubMed

The membrane-proximal external region (MPER) C-terminal segment and the transmembrane domain (TMD) of gp41 are involved in HIV-1 Env glycoprotein-mediated fusion and modulation of immune responses during viral infection. However, the atomic structure of this functional region remains unsolved. Here, based on the high-resolution NMR data obtained for peptides spanning the C-terminal segment of MPER and the TMD, we report two main findings: (i) the conformational variability of the TMD helix at a membrane-buried position; and (ii) the existence of an uninterrupted alpha-helix spanning MPER and the N-terminal region of the TMD. Thus, our structural data provide evidence for the bipartite organization of TMD predicted by previous molecular dynamics simulations and functional studies, but do not support the breaking of the helix at position Lys-683, as was suggested by some models to mark the initiation of the TMD anchor. Antibody binding energetics examined with isothermal titration calorimetry, and humoral responses elicited in rabbits by peptide-based vaccines further support the relevance of a continuous MPER-TMD helix for immune recognition. We conclude that the transmembrane anchor of HIV-1 Env is composed of two distinct subdomains: 1) an immunogenic helix at the N-terminus also involved in promoting membrane fusion; and 2) an immunosuppressive helix at the C-terminus, which might also contribute to the late stages of the fusion process. The unprecedented high-resolution structural data reported here may guide future vaccine and inhibitor developments.

The Atomic Structure of the HIV-1 gp41 Transmembrane Domain and its Connection to the Inmmunogenic Membrane-proximal External Region.,Apellaniz B, Rujas E, Serrano S, Morante K, Tsumoto K, Caaveiro JM, Jimenez MA, Nieva JL J Biol Chem. 2015 Mar 18. pii: jbc.M115.644351. PMID:25787074^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.